This invention relates to enzymatic disruption of the vitreoretinal interface and, more particularly, to enzymatic disinsertion or complete removal of the vitreous body in association with surgical vitrectomy.
The vitreous body, a connective tissue compartment which occupies four-fifths of the volume of the eye, provides structural and metabolic support for ocular tissues and assists in the maintenance of intraocular pressure while at the same time allowing light access to the retina. This structure is bound anteriorly by the lens and ciliary body epithelium and posteriorly by the retina. The vitreous exists as a semi-solid, highly transparent gel and is composed of approximately 99% water and 1% macromolecules including collagen, hyaluronic acid, a number of unidentified, soluble glycoproteins, sugars and various low molecular weight metabolites. The distribution of type II collagen, the major structural protein within the vitreous, is quite regular and essential for the mechanical properties of this highly diluted gel. During the earlier years of life, the vitreous is differentiated into a cortex of high density and a semifluid central vitreous; in early adolescence destruction of the vitreous framework begins, leading to the formation of liquified cavities and fibrillar strands within the vitreous gel during later years.
Normal anatomic attachments between the vitreous body and retina occur in a number of regions, although the molecular basis for normal vitreoretinal adhesion is still unknown (see FIG. 1). The zone of strongest vitreoretinal adherence, the vitreous base, straddles the ora serrata and measures approximately 3.2 mm in the anterior-to-posterior meridian (FIG. 1). Its anterior border is associated with the posterior pars plana; the posterior border expands gradually from the ora serrata towards the equator with age. The connection between the retinal basal lamina and the collagen fibrils in the region of the vitreous base is so strong in the normal human that, when the vitreous is pulled in an attempt to separate them, either the vitreous cortex breaks away from the rest of the vitreous or part of the cells of the retina and ciliary body break away from the ocular wall. In other words, the attachment is mechanically stronger than that of the vitreous gel itself. Other zones of vitreoretinal attachment, although weaker, exist at the borders of "cortical holes" including those around the optic disc ("peripallary"), around the fovea ("posterior vitreous base"), along major retinal vessels and at sights of developmental anomalies. Secondary sites of strong vitreoretinal attachment often develop at the border of degenerative or inflammatory lesions providing tractional pivot points on the surface of the retina which often cause its detachment.
Vitrectomy, the surgical removal of a portion of the vitreous body and/or associated "membranes" (epiretinal; fibrous), is indicated for the treatment or prevention of a variety of pathologic, operative, or postoperative conditions which, if untreated, can result in blindness. Typically, vitrectomy is performed secondary to complications which affect the normal vitreoretinal interface. These complications can be placed into three basic categories; 1) the development of secondary attachments between the vitreous and the retina, such as those which develop at sites of chorioretinal scars or in the vicinity of retinal neovascularization; 2) loss of normal adhesion between the retina and vitreous resulting in partial or complete vitreous detachment; and 3) the formation of cellular and/or fibrous membranes along the vitreoretinal interface and/or within the vitreous framework. Indications for vitreous surgery include proliferative retinopathy, complicated rhegmatogenous retinal detachment, epiretinal membrane formation, secondary (pathologic) vitreous detachment, vitreomacular traction, retinal detachment associated with retinopathy of prematurity, vitreous hemorrhage, perforating trauma, cataract removal, endophthalmitis, persistent hyperplastic primary vitreous, and a number of operative and posteroperative complications which affect the vitreous secondarily. The primary concern in most cases of vitreoretinal pathology is the production of retinal tears and ultimately, detachment of the retina. Retinal detachment, if not treated immediately, will lead to photoreceptor cell (those cells responsible for transduction of light impulses into electrical impulses) death and, consequently, loss of vision. For example, in cases of imcomplete vitreous detachment, the vitreous gel remains attached to the retina at the optic disc and/or the macula, and to the vitreous base. Secondary fibrous proliferation associated with these sites of adhesion leads to vitreopapillary and/or vitreomacular traction which can create tears in the retina.
Proliferative vitreoretinopathy (PVR), another example of a vitreoretinal abnormality, continues to be one of the most devastating types of vitreoretinal pathology leading to retinal detachment. In the most common type of PVR, that following retinal detachment, retinal pigment epithelial cells migrate into and proliferate within the vitreous scaffold, contributing to the formation of cellular (and fibrocellular) membranes which contract and cause retinal tears and/or retinal detachment. Peeling and/or delaminating these and other membranes from the retinal surface has become a standard procedure during vitrectomy. However, these procedures pose a great surgical risk and most often result in the creation of retinal tears and detachment. In addition, retinal tears can be created when the surgeon comes too close to the retinal surface with various instruments or when too much suction is applied on the vitreous at sites of firm vitreoretinal adhesion.
Despite the continued development and improvement of surgical techniques, creation of retinal tears and detachment is often unavoidable, due largely to our lack of knowledge pertaining to the fundamental mechanism and biology of vitreoretinal attachment. Major advances in the prevention and management of retinal detachment resulting from abnormal vitreoretinal adhesion will require detailed anatomical, biochemical and physiological research on the vitreoretinal interface if the causes of abnormal vitreous adhesion and shrinkage are to be understood.
The prior art is devoid of any disclosure of methodology for effectively insuring the selective and complete disinsertion of the ocular vitreous body, epiretinal membranes and/or fibrocellular membranes from the neural retina, ciliary epithelium, and posterior lens surface of the eye as an adjunct to vitrectomy.
Moorhead et al. (Retina, 5:98-100, 1985; Arch. Ophthalmol. 101:265-274, 1983) discloses enzyme-assisted vitrectomy using bacterial collagenase (Clostridiopeptidase A) for facilitating removal of fibroproliferative tissue and epiretinal membranes by partial digestion of the fibrous membrane prior to removal. The bacterial collagenase is stated to act by partial digestion of the fibrous membrane, thereby facilitating the removal of intravitreal fibroproliferative tissue.
Cope U.S. Pat. No. 4,174,389 discloses a method for the selective lysis of collagen fibrils located in the vitreous of the ocular region of a mammal through the administration of collagenase. According to the Cope patent, a significant amount of liquifaction occurs when the vitreous is contacted with collagenase.
Shehab et al. (Invest. Ophthalmol. Vis. Sci. Suppl. 27:317, 1986) disclose the effectiveness of six enzymes, including collagenase and chondroitinase ABC, to liquify the vitreous of freshly enucleated pig eyes by measuring the time required for total vitrectomy. Based upon the results obtained, Shehab et al. utilized protease-containing chondroitinase ABC.
Brown U.S. Pat. No. 4,696,816 discloses a method for the treatment of intervertebral disc displacement in humans using the enzyme chondroitinase ABC or AC to bring about the selective chemonucleolysis of the nucleus pulposus which contains proteoglycans and randomly dispersed collagen fibers.
Yamagata et al. (Chem. Abstracts, 68:84511g, 1968) disclose that the enzyme chondroitinase ABC selectively degrades chondroitin sulfates A, B, and C at pH 8.
There remains a need for improved methods for complete enzymatic removal or disinsertion of vitreous body as an adjunct to surgical vitrectomy, which methods are based upon the identification of the component(s) responsible for vitreoretinal adhesion.